Solifenacin is represented by the following formula (I):
and is chemically called (1R,3′R)-3′-quinuclidinyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinoline carboxylate.
It is reported that a series of quinuclidine derivatives including solifenacin or salts thereof have an excellent selective antagonistic action against muscarine M3 receptors and are useful as prophylactic or therapeutic agents of urinary diseases such as nervous pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, bladder contracture, and chronic cystitis as well as respiratory diseases such as chronic occlusive lung diseases, chronic bronchitis, asthma and rhinitis (see patent reference 1).
A manufacturing process of solifenacin hydrochloride is described in Example 8 in the patent reference 1, wherein the crystal resulting from crystallization in a mixture solvent of acetonitrile and diethyl ether has a melting point of 212 to 214° C. and has a specific rotation ([α]25D of 98.1 (c=1.00, EtOH).
However, the patent reference 1 includes no description or suggestion about significant degradation over time of amorphous solifenacin or an amorphous salt thereof or solifenacin succinate as an active pharmaceutical ingredient in a formulation when solifenacin succinate product is formulated by a general pharmaceutical manufacturing process.
Non-patent reference 1 publicly issued by the Japanese Ministry of Health, Labor and Welfare in June, 2003 includes the description about the specification of drug products, namely the concept about degradation products (impurities) in new drug products as observed at stability tests. According to the reference, the threshold of a degradation products requiring safety qualification in a drug product is a lower one of either 1.0% as the percentage of the degradation product contained in a drug substance or 50 μg as the total daily intake of the degradation product, when the amount of the drug substance to be administered per day is less than 10 mg. When the amount of the drug substance to be administered per day is 10 mg or more to 100 mg or less, the threshold of a degradation product requiring safety qualification in a drug products is a lower one of either 0.5% as the percentage of the degradation product contained in a drug substance or 200 μg as the total daily intake of the degradation product. Therefore, the specification of a degradation product as can be determined with no requirement of any safety qualification of the degradation product is generally 1.0% or less as the percentage of the degradation product contained in a drug substance, when the formulation is for example at a 5-mg content of the drug substance. When the formulation is for example at a 10-mg content of the drug substance, the percentage of the degradation product contained in the drug substance is 0.5% or less.
Solifenacin formulations, currently planned in a market on the basis of clinical test results, are 2.5-mg, 5-mg, and 10-mg tablets. For these formulations to have the stability described in the non-patent reference 1, it was considered that the amount of the main degradation product (abbreviated as F1 hereinafter) of solifenacin succinate to the total amount of solifenacin succinate and degradation products thereof should be set at 0.5% or less and that the amount should be controlled to 0.4% or less, considering lot-to-lot variation and test errors.
Patent reference 1: Specification of EP 801 067
Non-patent reference 1: Notification No. 0624001 issued by Japanese Committee of Pharmaceutical Affairs, “Revision of Guideline about Impurities in New Drug Products containing Novel Active Pharmaceutical Ingredients”